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Cancers
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NF-kappaB signalling pathway
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NF-kappaB signalling pathway

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 July 2019) | Viewed by 67435

Special Issue Editor

Prof. Dr. Alexander Arlt

E-Mail Website
Guest Editor
Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany
Interests: NF-kappaB; cell death; pancreatic cancer; inflammation

Special Issue Information

Dear Colleagues,

This Special Issue is about the NF-kappaB signalling pathway and its pleiotropic effects on different aspects of cancer, including oncogenesis and therapy resistance. Originally described in the context of inflammation, a huge amount of excellent work has been done to describe the role of NF-kappab as a central tumor-promoting signalling pathway in inflammation-associated cancer. Furthermore, components of the pathway and the NF-kappab subunits itself are frequently genetically altered in tumors. In addition, emerging data demonstrate that NF-kappab signalling is involved in different aspects of therapy resistance. In addition to the tumor cell-intrinsic function, this signalling pathway has been shown to be crucial in mediating onco-immuno signalling and in the regulation of the tumor microenvironment of several tumor entities. Furthermore, NF-kappaB is involved in aspects like metabolism, immunity, epigenetic regulation, and all kinds of cell deaths, predestining this signalling pathway to be one of the most attractive molecular targets in cancer therapy. However, some very eloquent publications have raised the issue that under certain conditions NF-kappaB can act as a direct tumor suppressor and also mediate anti-tumor immune responses, presenting a dilemma when designing NF-kappaB targeting anti-tumor therapies.

Here, we welcome papers outlining the recent anti- but also the pro-tumorigenic role of NF-kappaB.

Prof. Dr. Alexander Arlt
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 163 KiB  
Editorial
Do We Really Need Another Special Issue on NF-κB in Cancer and Inflammation?
by Claudia Geismann and Alexander Arlt
Cancers 2019, 11(12), 1978; https://doi.org/10.3390/cancers11121978 - 9 Dec 2019
Viewed by 1835
Abstract
This series of 10 articles (four original articles, six reviews) is presented by international leaders in the field of NF-κB signaling in cancer and inflammation [...] Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)

Research

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20 pages, 6651 KiB  
Article
Single-Cell Analysis of Multiple Steps of Dynamic NF-κB Regulation in Interleukin-1α-Triggered Tumor Cells Using Proximity Ligation Assays
by Christin Mayr-Buro, Eva Schlereth, Knut Beuerlein, Ulas Tenekeci, Johanna Meier-Soelch, M. Lienhard Schmitz and Michael Kracht
Cancers 2019, 11(8), 1199; https://doi.org/10.3390/cancers11081199 - 16 Aug 2019
Cited by 7 | Viewed by 4119
Abstract
The frequently occurring heterogeneity of cancer cells and their functional interaction with immune cells in the tumor microenvironment raises the need to study signaling pathways at the single cell level with high precision, sensitivity, and spatial resolution. As aberrant NF-κB activity has been [...] Read more.
The frequently occurring heterogeneity of cancer cells and their functional interaction with immune cells in the tumor microenvironment raises the need to study signaling pathways at the single cell level with high precision, sensitivity, and spatial resolution. As aberrant NF-κB activity has been implicated in almost all steps of cancer development, we analyzed the dynamic regulation and activation status of the canonical NF-κB pathway in control and IL-1α-stimulated individual cells using proximity ligation assays (PLAs). These systematic experiments allowed the visualization of the dynamic dissociation and re-formation of endogenous p65/IκBα complexes and the nuclear translocation of NF-κB p50/p65 dimers. PLA combined with immunostaining for p65 or with NFKBIA single molecule mRNA-FISH facilitated the analysis of (i) further levels of the NF-κB pathway, (i) its functionality for downstream gene expression, and (iii) the heterogeneity of the NF-κB response in individual cells. PLA also revealed the interaction between NF-κB p65 and the P-body component DCP1a, a new p65 interactor that contributes to efficient p65 NF-κB nuclear translocation. In summary, these data show that PLA technology faithfully mirrored all aspects of dynamic NF-κB regulation, thus allowing molecular diagnostics of this key pathway at the single cell level which will be required for future precision medicine. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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Graphical abstract

10 pages, 3346 KiB  
Article
An NF-kappaB- and IKK-Independent Function of NEMO Prevents Hepatocarcinogenesis by Suppressing Compensatory Liver Regeneration
by Christiane Koppe, Florian Reisinger, Karina Wehr, Mihael Vucur, Christian Trautwein, Frank Tacke, Mathias Heikenwalder and Tom Luedde
Cancers 2019, 11(7), 999; https://doi.org/10.3390/cancers11070999 - 17 Jul 2019
Cited by 14 | Viewed by 4212
Abstract
The I-κB-Kinase (IKK) complex represents a central signaling nexus in the TNF-dependent activation of the pro-inflammatory NF-κB pathway. However, recent studies suggested that the distinct IKK subunits (IKKα, IKKβ, and NEMO) might withhold additional NF-κB-independent functions in inflammation and cancer. Here, we generated [...] Read more.
The I-κB-Kinase (IKK) complex represents a central signaling nexus in the TNF-dependent activation of the pro-inflammatory NF-κB pathway. However, recent studies suggested that the distinct IKK subunits (IKKα, IKKβ, and NEMO) might withhold additional NF-κB-independent functions in inflammation and cancer. Here, we generated mice lacking all three IKK subunits in liver parenchymal cells (LPC) (IKKα/β/NEMOLPC-KO) and compared their phenotype with mice lacking both catalytic subunits (IKKα/βLPC-KO), allowing to functionally dissect putative I-κB-Kinase-independent functions of the regulatory subunit NEMO. We show that the additional deletion of NEMO rescues IKKα/βLPC-KO mice from lethal cholestasis and biliary ductopenia by triggering LPC apoptosis and inducing a strong compensatory proliferation of LPC including cholangiocytes. Beyond this beneficial effect, we show that increased hepatocyte cell-death and compensatory proliferation inhibit the activation of LPC-necroptosis but trigger spontaneous hepatocarcinogenesis in IKKα/β/NEMOLPC-KO mice. Collectively, our data show that free NEMO molecules unbound to the catalytic IKK subunits control LPC programmed cell death pathways and proliferation, cholestasis and hepatocarcinogenesis independently of an IKK-related function. These findings support the idea of different functional levels at which NEMO controls inflammation and cancer in the liver. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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18 pages, 1317 KiB  
Article
Functional Toll-Like Receptors (TLRs) Are Expressed by a Majority of Primary Human Acute Myeloid Leukemia Cells and Inducibility of the TLR Signaling Pathway Is Associated with a More Favorable Phenotype
by Annette K. Brenner and Øystein Bruserud
Cancers 2019, 11(7), 973; https://doi.org/10.3390/cancers11070973 - 11 Jul 2019
Cited by 29 | Viewed by 4047
Abstract
Acute myeloid leukemia (AML) is a highly heterogeneous disease with regard to biological characteristics and receptor expression. Toll-like receptors (TLRs) are upstream to the transcription factor NFκB and part of the innate immune system. They are differentially expressed on AML blasts, and during [...] Read more.
Acute myeloid leukemia (AML) is a highly heterogeneous disease with regard to biological characteristics and receptor expression. Toll-like receptors (TLRs) are upstream to the transcription factor NFκB and part of the innate immune system. They are differentially expressed on AML blasts, and during normal hematopoiesis they initiate myeloid differentiation. In this study, we investigated the response upon TLR stimulation in an AML cohort (n = 83) by measuring the increase of NFκB-mediated cytokine secretion. We observed that TLR4 is readily induced in most patients, while TLR1/2 response was more restricted. General response to TLR stimulation correlated with presence of nucleophosmin gene mutations, increased mRNA expression of proteins, which are part of the TLR signaling pathway and reduced expression of transcription-related proteins. Furthermore, signaling via TLR1/2 appeared to be linked with prolonged patient survival. In conclusion, response upon TLR stimulation, and especially TLR1/2 induction, seems to be part of a more favorable phenotype, which also is characterized by higher basal cytokine secretion and a more mature blast population. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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19 pages, 5080 KiB  
Article
Chemotherapeutic Drugs Inhibiting Topoisomerase 1 Activity Impede Cytokine-Induced and NF-κB p65-Regulated Gene Expression
by Tabea Riedlinger, Marek Bartkuhn, Tobias Zimmermann, Sandra B. Hake, Andrea Nist, Thorsten Stiewe, Michael Kracht and M. Lienhard Schmitz
Cancers 2019, 11(6), 883; https://doi.org/10.3390/cancers11060883 - 25 Jun 2019
Cited by 10 | Viewed by 4484
Abstract
Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian, small cell lung and cervical cancer. As torsional stress is generated during transcription by progression of RNA polymerase II [...] Read more.
Inhibitors of DNA topoisomerase I (TOP1), an enzyme relieving torsional stress of DNA by generating transient single-strand breaks, are clinically used to treat ovarian, small cell lung and cervical cancer. As torsional stress is generated during transcription by progression of RNA polymerase II through the transcribed gene, we tested the effects of camptothecin and of the approved TOP1 inhibitors Topotecan and SN-38 on TNFα-induced gene expression. RNA-seq experiments showed that inhibition of TOP1 but not of TOP2 activity suppressed the vast majority of TNFα-triggered genes. The TOP1 effects were fully reversible and preferentially affected long genes. TNFα stimulation led to inducible recruitment of TOP1 to the gene body of IL8, where its inhibition by camptothecin reduced transcription elongation and also led to altered histone H3 acetylation. Together, these data show that TOP1 inhibitors potently suppress expression of proinflammatory cytokines, a feature that may contribute to the increased infection risk occurring in tumor patients treated with these agents. On the other hand, TOP1 inhibitors could also be considered as a therapeutic option in order to interfere with exaggerated cytokine expression seen in several inflammatory diseases. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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Review

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17 pages, 948 KiB  
Review
NF-κB Dependent Chemokine Signaling in Pancreatic Cancer
by Claudia Geismann, Heiner Schäfer, Jan-Paul Gundlach, Charlotte Hauser, Jan-Hendrik Egberts, Günter Schneider and Alexander Arlt
Cancers 2019, 11(10), 1445; https://doi.org/10.3390/cancers11101445 - 26 Sep 2019
Cited by 28 | Viewed by 5198
Abstract
Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the [...] Read more.
Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the second leading cause of cancer-related death in 2020 in the US. In addition to tumor cell intrinsic resistance mechanisms, this disease exhibits a complex stroma consisting of fibroblasts, immune cells, neuronal and vascular cells, along with extracellular matrix, all conferring therapeutic resistance by several mechanisms. The NF-κB pathway is involved in both the tumor cell-intrinsic and microenvironment-mediated therapeutic resistance by regulating the transcription of a plethora of target genes. These genes are involved in nearly all scenarios described as the hallmarks of cancer. In addition to classical regulators of apoptosis, NF-κB regulates the expression of chemokines and their receptors, both in the tumor cells and in cells of the microenvironment. These chemokines mediate autocrine and paracrine loops among tumor cells but also cross-signaling between tumor cells and the stroma. In this review, we will focus on NF-κB-mediated chemokine signaling, with an emphasis on therapy resistance in pancreatic cancer. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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16 pages, 626 KiB  
Review
NF-κB Signaling in Ovarian Cancer
by Brittney S. Harrington and Christina M. Annunziata
Cancers 2019, 11(8), 1182; https://doi.org/10.3390/cancers11081182 - 15 Aug 2019
Cited by 91 | Viewed by 9737
Abstract
The NF-κB signaling pathway is a master and commander in ovarian cancer (OC) that promotes chemoresistance, cancer stem cell maintenance, metastasis and immune evasion. Many signaling pathways are dysregulated in OC and can activate NF-κB signaling through canonical or non-canonical pathways which have [...] Read more.
The NF-κB signaling pathway is a master and commander in ovarian cancer (OC) that promotes chemoresistance, cancer stem cell maintenance, metastasis and immune evasion. Many signaling pathways are dysregulated in OC and can activate NF-κB signaling through canonical or non-canonical pathways which have both overlapping and distinct roles in tumor progression. The activation of canonical NF-κB signaling has been well established for anti-apoptotic and immunomodulatory functions in response to the tumor microenvironment and the non-canonical pathway in cancer stem cell maintenance and tumor re-initiation. NF-κB activity in OC cells helps to create an immune-evasive environment and to attract infiltrating immune cells with tumor-promoting phenotypes, which in turn, drive constitutive NF-κB activation in OC cells to promote cell survival and metastasis. For these reasons, NF-κB is an attractive target in OC, but current strategies are limited and broad inhibition of this major signaling pathway in normal physiological and immunological functions may produce unwanted side effects. There are some promising pre-clinical outcomes from developing research to target and inhibit NF-κB only in the tumor-reinitiating cancer cell population of OC and concurrently activate canonical NF-κB signaling in immune cells to promote anti-tumor immunity. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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19 pages, 4368 KiB  
Review
Context-Dependent Role of NF-κB Signaling in Primary Liver Cancer—from Tumor Development to Therapeutic Implications
by Carolin Czauderna, Darko Castven, Friederike L. Mahn and Jens U. Marquardt
Cancers 2019, 11(8), 1053; https://doi.org/10.3390/cancers11081053 - 25 Jul 2019
Cited by 52 | Viewed by 9159
Abstract
Chronic inflammatory cell death is a major risk factor for the development of diverse cancers including liver cancer. Herein, disruption of the hepatic microenvironment as well as the immune cell composition are major determinants of malignant transformation and progression in hepatocellular carcinomas (HCC). [...] Read more.
Chronic inflammatory cell death is a major risk factor for the development of diverse cancers including liver cancer. Herein, disruption of the hepatic microenvironment as well as the immune cell composition are major determinants of malignant transformation and progression in hepatocellular carcinomas (HCC). Considerable research efforts have focused on the identification of predisposing factors that promote induction of an oncogenic field effect within the inflammatory liver microenvironment. Among the most prominent factors involved in this so-called inflammation-fibrosis-cancer axis is the NF-κB pathway. The dominant role of this pathway for malignant transformation and progression in HCC is well documented. Pathway activation is significantly linked to poor prognostic traits as well as stemness characteristics, which places modulation of NF-κB signaling in the focus of therapeutic interventions. However, it is well recognized that the mechanistic importance of the pathway for HCC is highly context and cell type dependent. While constitutive pathway activation in an inflammatory etiological background can significantly promote HCC development and progression, absence of NF-κB signaling in differentiated liver cells also significantly enhances liver cancer development. Thus, therapeutic targeting of NF-κB as well as associated family members may not only exert beneficial effects but also negatively impact viability of healthy hepatocytes and/or cholangiocytes, respectively. The review presented here aims to decipher the complexity and paradoxical functions of NF-κB signaling in primary liver and non-parenchymal cells, as well as the induced molecular alterations that drive HCC development and progression with a particular focus on (immune-) therapeutic interventions. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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26 pages, 879 KiB  
Review
The Unsolved Puzzle of c-Rel in B Cell Lymphoma
by Maike Kober-Hasslacher and Marc Schmidt-Supprian
Cancers 2019, 11(7), 941; https://doi.org/10.3390/cancers11070941 - 4 Jul 2019
Cited by 9 | Viewed by 4987
Abstract
Aberrant constitutive activation of Rel/NF-κB transcription factors is a hallmark of numerous cancers. Of the five Rel family members, c-Rel has the strongest direct links to tumorigenesis. c-Rel is the only member that can malignantly transform lymphoid cells in vitro. Furthermore, c-Rel is [...] Read more.
Aberrant constitutive activation of Rel/NF-κB transcription factors is a hallmark of numerous cancers. Of the five Rel family members, c-Rel has the strongest direct links to tumorigenesis. c-Rel is the only member that can malignantly transform lymphoid cells in vitro. Furthermore, c-Rel is implicated in human B cell lymphoma through the frequent occurrence of REL gene locus gains and amplifications. In normal physiology, high c-Rel expression predominates in the hematopoietic lineage and a diverse range of stimuli can trigger enhanced expression and activation of c-Rel. Both expression and activation of c-Rel are tightly regulated on multiple levels, indicating the necessity to keep its functions under control. In this review we meta-analyze and integrate studies reporting gene locus aberrations to provide an overview on the frequency of REL gains in human B cell lymphoma subtypes, namely follicular lymphoma, diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, and classical Hodgkin lymphoma. We also summarize current knowledge on c-Rel expression and protein localization in these human B cell lymphomas and discuss the co-amplification of BCL11A with REL. In addition, we highlight and illustrate key pathways of c-Rel activation and regulation with a specific focus on B cell biology. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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20 pages, 1261 KiB  
Review
NF-κB/Rel Transcription Factors in Pancreatic Cancer: Focusing on RelA, c-Rel, and RelB
by Derya Kabacaoglu, Dietrich A. Ruess, Jiaoyu Ai and Hana Algül
Cancers 2019, 11(7), 937; https://doi.org/10.3390/cancers11070937 - 4 Jul 2019
Cited by 40 | Viewed by 9294
Abstract
Regulation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Rel transcription factors (TFs) is extremely cell-type-specific owing to their ability to act disparately in the context of cellular homeostasis driven by cellular fate and the microenvironment. This is also valid for tumor cells [...] Read more.
Regulation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Rel transcription factors (TFs) is extremely cell-type-specific owing to their ability to act disparately in the context of cellular homeostasis driven by cellular fate and the microenvironment. This is also valid for tumor cells in which every single component shows heterogenic effects. Whereas many studies highlighted a per se oncogenic function for NF-κB/Rel TFs across cancers, recent advances in the field revealed their additional tumor-suppressive nature. Specifically, pancreatic ductal adenocarcinoma (PDAC), as one of the deadliest malignant diseases, shows aberrant canonical-noncanonical NF-κB signaling activity. Although decades of work suggest a prominent oncogenic activity of NF-κB signaling in PDAC, emerging evidence points to the opposite including anti-tumor effects. Considering the dual nature of NF-κB signaling and how it is closely linked to many other cancer related signaling pathways, it is essential to dissect the roles of individual Rel TFs in pancreatic carcinogenesis and tumor persistency and progression. Here, we discuss recent knowledge highlighting the role of Rel TFs RelA, RelB, and c-Rel in PDAC development and maintenance. Next to providing rationales for therapeutically harnessing Rel TF function in PDAC, we compile strategies currently in (pre-)clinical evaluation. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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22 pages, 1459 KiB  
Review
A Role for NF-κB in Organ Specific Cancer and Cancer Stem Cells
by Christian Kaltschmidt, Constanze Banz-Jansen, Tahar Benhidjeb, Morris Beshay, Christine Förster, Johannes Greiner, Eckard Hamelmann, Norbert Jorch, Fritz Mertzlufft, Jesco Pfitzenmaier, Matthias Simon, Jan Schulte am Esch, Thomas Vordemvenne, Dirk Wähnert, Florian Weissinger, Ludwig Wilkens and Barbara Kaltschmidt
Cancers 2019, 11(5), 655; https://doi.org/10.3390/cancers11050655 - 11 May 2019
Cited by 90 | Viewed by 9280
Abstract
Cancer stem cells (CSCs) account for tumor initiation, invasiveness, metastasis, and recurrence in a broad range of human cancers. Although being a key player in cancer development and progression by stimulating proliferation and metastasis and preventing apoptosis, the role of the transcription factor [...] Read more.
Cancer stem cells (CSCs) account for tumor initiation, invasiveness, metastasis, and recurrence in a broad range of human cancers. Although being a key player in cancer development and progression by stimulating proliferation and metastasis and preventing apoptosis, the role of the transcription factor NF-κB in cancer stem cells is still underestimated. In the present review, we will evaluate the role of NF-κB in CSCs of glioblastoma multiforme, ovarian cancer, multiple myeloma, lung cancer, colon cancer, prostate cancer, as well as cancer of the bone. Next to summarizing current knowledge regarding the presence and contribution of CSCs to the respective types of cancer, we will emphasize NF-κB-mediated signaling pathways directly involved in maintaining characteristics of cancer stem cells associated to tumor progression. Here, we will also focus on the status of NF-κB-activity predominantly in CSC populations and the tumor mass. Genetic alterations leading to NF-κB activity in glioblastoma, ependymoma, and multiple myeloma will be discussed. Full article
(This article belongs to the Special Issue NF-kappaB signalling pathway)
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